As the demographics of the modern world skew older, understanding and mitigating the effects of aging is increasingly important within biomedical research. Recent studies in model organisms demonstrate that the aging process is frequently modified by an organism’s ability to perceive and respond to changes in its environment. Many well-studied pathways that influence aging involve sensory cells, frequently neurons, that signal to peripheral tissues and promote survival during the presence of stress. Importantly, this activation of stress response pathways is often sufficient to improve health and longevity even in the absence of stress. Here, we review the current landscape of research highlighting the importance of cell non-autonomous signaling in modulating aging from C. elegans to mammals. We also discuss emerging concepts including retrograde signaling, approaches to mapping these networks, and development of potential therapeutics.

An organism’s ability to perceive and respond to changes in its environment is crucial for its health and survival. Here we reveal how the most well-studied longevity intervention, dietary restriction, acts in-part through a cell non-autonomous signaling pathway that is inhibited by the presence of attractive smells. Using an intestinal reporter for a key gene induced by dietary restriction but suppressed by attractive smells, we identify three compounds that block food odor effects in C. elegans, thereby increasing longevity as dietary restriction mimetics. These compounds clearly implicate serotonin and dopamine in limiting lifespan in response to food odor. We further identify a chemosensory neuron that likely perceives food odor, an enteric neuron that signals through the serotonin receptor 5-HT1A/SER-4, and a dopaminergic neuron that signals through the dopamine receptor DRD2/DOP-3. Aspects of this pathway are conserved in D. melanogaster. Thus, blocking food odor signaling through antagonism of serotonin or dopamine receptors is a plausible approach to mimic the benefits of dietary restriction.

Flavin containing monooxygenases (FMOs) are promiscuous enzymes known for metabolizing a wide range of exogenous compounds. In C. elegans, fmo-2 expression increases lifespan and healthspan downstream of multiple longevity-promoting pathways through an unknown mechanism. Here, we report that, beyond its classification as a xenobiotic enzyme, fmo-2 expression leads to rewiring of endogenous metabolism principally through changes in one carbon metabolism (OCM). These changes are likely relevant, as we find that genetically modifying OCM enzyme expression leads to alterations in longevity that interact with fmo-2 expression. Using computer modeling, we identify decreased methylation as the major OCM flux modified by FMO-2 that is sufficient to recapitulate its longevity benefits. We further find that tryptophan is decreased in multiple mammalian FMO overexpression models and is a validated substrate for FMO-2. Our resulting model connects a single enzyme to two previously unconnected key metabolic pathways and provides a framework for the metabolic interconnectivity of longevity-promoting pathways such as dietary restriction. FMOs are well-conserved enzymes that are also induced by lifespan-extending interventions in mice, supporting a conserved and important role in promoting health and longevity through metabolic remodeling.

An organism’s ability to perceive and respond to changes in its environment is crucial for its health and survival. Our approach to identify molecular mechanisms of aging is to focus on common mechanisms downstream of multiple pathways. This approach led to our discovery of a gene, flavin-containing monooxygenase (fmo)-2, that is both necessary and sufficient to increase lifespan and healthspan downstream of several longevity interventions, including dietary restriction and hypoxia. Surprisingly, we also find that in both hypoxia and dietary restriction models, fmo-2 is induced by cell non-autonomous signaling pathways, consistent with the worms’ perceiving the stress (e.g. low oxygen, lack of food) and changing physiology as a result. Our current work focuses on 1) the signaling networks that regulate stress perception and integrate multiple signals to change physiology, and 2) the mechanism of FMO-2-mediated longevity. Our new data suggest that these cell non autonomous networks pathways utilize both overlapping and distinct signaling mechanisms to converge on upregulation of the same gene. They also suggest that these pathways can be manipulated by small molecule drugs to increase lifespan by “tricking” the organism into activating stress response networks. We further find that FMO enzyme expression has a drastic effect on endogenous metabolism, primarily through tryptophan and one carbon metabolism. Ultimately, we aim to leverage our results in a translational framework to identify key signals, genes, and mechanisms where organisms respond to the perception of environmental stress to improve health and slow aging.